The B cell immune response in the elderly is characterized by the production of low affinity antibodies and by the production of autoreactive antibodies. This results in diminished protection against infections and in increased incidence of autoimmune diseases in the elderly. Defects in the immune response have been extensively studied in the mouse. Little is known, however, about B cell defects in the human. Here, we propose to analyze defects in the human humoral immune response. In particular, we want to analyze defects associated with affinity maturation in the elderly. First, we will determine whether defects involve B cell development by analyzing B cell subpopulations in tonsils. Additionally, antibodies expressed by these various subpopulations will be sequenced and Vh gene utilization will be analyzed. Data on B cell subpopulations and antibody sequences will be compared to data previously obtained in similar conditions from young adult tonsils. Second, we will determine whether defects are at the B and/or T cell level by analyzing the ability of B and T cells from the elderly to mediate somatic mutation. For this, we will use an in vitro assay. Third, we will determine whether aging influences immunoglobulin gene segment utilization and antigenic selection using a human immunoglobulin heavy chain transgenic mini-locus model we developed. This project is likely to provide important information on the defects involved in antibody repertoire shaping in aging humans. The research will complement that in Project III which will analyze defects in early B cell development in elderly humans and is consistent with the overall Program Project theme of lymphocyte development.